1. Field of the Invention
The invention relates to a method of treating pulmonary dysfunction and dependence on mechanical ventilation in a mammal which comprises administration of growth hormone (GH) to said mammal. In one embodiment the invention pertains to critical care medicine and the treatment of spinal cord injury, chronic obstructive pulmonary disease, and/or sepsis resulting in ventilator dependency. In another embodiment, the invention is directed to improving pulmonary function in other pulmonary diseases, including pneumonia, chronic asthma, emphysema, and tuberculosis.
2. Description of the Background Art
A major problem in critical care medicine is the presence of pulmonary dysfunction. Often, such dysfunction requires that patients be administered mechanical ventilatory support. A further difficulty encountered in such patients is the inability to wean them from ventilators. "Weaning" a patient from ventilatory support ranges from a simple to an extremely complex process. The timing of withdrawal of ventilatory support is critical and criteria have been established to aid in this decision (Hodgkin et al., Crit. Care Med. 2:96 (1974)). The optimization of number of factors is considered necessary before weaning is initiated. Such factors include the correction of anemias, low cardiac output, fluid imbalance, arrhythmias, fever, electrolyte abnormalities, infection, and acid-base disturbances. Specific respiratory physiologic parameters are required to indicate adequate mechanical capability: Vital capacity (&gt;10-15 ml/kg); forced expiratory volume (&gt;10 ml/kg/sec); peak inspiratory pressure (-20 to -30 cm H.sub.2 O); and spontaneous resting minute ventilation (&lt;10 L/min).
The concomitant use of intermittent mandatory ventilation (IMV) permits patients to increase muscle strength and improve lung function while gradually undergoing the transition.
Despite advances in respiratory management, patients with thoracic injuries, pulmonary infections, neuromuscular disorders, chronic obstructive lung disease or severe debility complicated by sepsis, are often difficult to wean from mechanical ventilatory support. Earlier weaning from such support carries with it a major economic savings due to the high cost of prolonged intensive care.
Pulmonary problems related to the primary disease are complicated by catabolic responses to infection and injury, muscle wasting following pharmacologic paralysis and bed rest, and the difficulties associated with appropriate nutritional support while maintaining adequate gas exchange (Pingleton et al., J.A.M.A. 257:3094-99 (1987)). Weaning from mechanical ventilatory support may be especially difficult during administration of total parenteral nutrition (TPN). The marked increase of CO.sub.2 production accompanying the large glucose load of TPN can precipitate respiratory distress. Use of intravenous fat emulsions, which are oxidized with a respiratory quotient of 0.7, (compared to 1.0 for glucose), has been suggested as a means of minimizing CO.sub.2 production in patients receiving TPN, especially in patients with compromised respiratory function (Askanazi et al., Anesthesiology 54:373-377 (1981)).
Malnutrition is common in patients with chronic lung disease; 40% of patients with chronic obstructive pulmonary disease (COPD) experience progressive weight loss (Goldstein et al., Clin. Chest Med. 7:141-151 (1986). The development of malnutrition exacerbates the already existing functional impairments of COPD, such as reduced respiratory muscle strength, and decreased diaphragm mass. Therefore a balance must be struck between the aggressive nutritional support required to improve respiratory muscle function and the metabolic demand thus created, which increases the respiratory workload. Goldstein et al. (ibid.) found that refeeding of COPD patients must be performed preventatively, at the start of weight loss. Patients with long term weight loss and end-stage COPD are unable to tolerate increased metabolic demand, and, thus, cannot improve respiratory and skeletal muscle strength through refeeding. An ideal solution to this problem is yet to be found.
In a study examining 6 COPD patients with malnutrition, Suchner et al. (Anesthesiology 6:A421, 1988) found that treatment with GH (30 .mu.g/day s.c.) in addition to TPN led to no improvement in muscle function, although nitrogen retention and lean body mass still increased. The authors concluded that GH therapy added to TPN may, at least, reduce refeeding-associated complications in COPD patients.
Many patients who fail to wean from the ventilator demonstrate diminished strength of the thoracic and extrathoracic musculature, resulting in poor inspiratory pressure, diminished movement of the thoracic cage, and an inability to insufflate the lungs. Such problems are seen in spinal cord injury patients suffering from quadriplegia, due to acute denervation of thoracic and abdominal muscles. Furthermore, pneumonia and pulmonary emboli frequently complicate the clinical course of quadriplegics during acute recovery from their injury. Progressive weight loss, atrophy of skeletal muscles, and increased nitrogen excretion follow spinal cord transection (Cooper et al. J. Clin. Endocrinol 10:858-870, 1950), with loss of muscle greatest in quadriplegics (Shizgal et al., J. Parent. Ent. Nutr. 10:364-368, 1986). Frequent overfeeding of spinal cord injury patients causes increases in body fat (Greenway et al., Paraplegia 7:301-317, 1970).
In patients without such neurological impairment, use of IMV (Luce et al., Chest 79:678-685, 1981) or nutritional support (Pingleton et al., J.A.M.A. 257:3094-99 (1987); Wilson et al., Am. Rev. Respir. Dis. 131:672-77 (1986)) has led to strengthening of thoracic muscles. Kelly et al., Amer. Rev. Respir. Dis. 130:33-37 (1984), reported a correlation between restoration of lean body mass (through nutritional support) and improvements in pulmonary function.